Assessment of immunosuppressant drug carcinogenicity: standard and alternative animal models

Abstract

Drugs intended for use in preventing allograft rejection in transplant patients are likely to be administered chroni-cally; thus, it is normally expected that sponsors would conduct nonclinical studies to determine the carcinogenic potential of candidate compounds. For pharmaceuticals other than biologic agents, this would mean that rodent carcinogenicity bioassays would be performed under most circumstances. Immunosuppressant drugs have presented unique challenges with respect to the issue of carcino-genicity bioassays. The pharmacological activity of ther-apeutic immunosuppressants is thought to make them highly likely to act as promoters/cocarcinogens, even in the absence of genotoxic activity. Thus, it is assumed that this class of drug would represent a carcinogenic hazard in the absence of confirmatory standard rodent bioassay data. In addition, rodents typically have been sensitive to the pharmacological/toxicological effects of immunosup-pressants. It has proven to be difficult, therefore, to conduct life-time bioassays at doses reasonably equiva-lent to those that would be used clinically. For this and other reasons, alternative models might be more appro-priate for risk assessment with this class of drugs.